tbuckley/cabot-search huggingface dataset:
Abstract 2070: Accelerated somatic mutation calling tool for whole-genome and whole-exome sequencing data from heterogenous tumor samples
Authors: Shuangxi Ji, Tong Zhu, Ankit Sethia, Matthew D. Montierth, Wenyi Wang
Journal: Cancer Research (2023)

Abstract As constantly improving in capacity and reducing in price, genomic sequencing is becoming a routine part of medical practice for cancer patients. Variant calling in sequencing data is a fundamental prerequisite for any downstream analysis, thus playing a critical role in both basic research and clinical care of cancers. However, it remains notably time-consuming for most available tools (e.g., ~2 days for MuSE 1.0 and MuTect2 to complete running on one tumor-normal pair of whole-genome sequencing (WGS) data). Here, we launch MuSE 2.0, which maintains the same input and output as our previously released MuSE 1.0, but speeds up significantly for both whole-exome sequencing (WES) and WGS data. MuSE 2.0 employs a multithreaded producer-consumer model and the OpenMP library for parallel computing, including parsing and uncompressing reads from BAM files, detecting and filtering variants, and writing output. Using sample data from ICGC and TCGA, we have benchmarked the speed performance of MuSE 2.0 against MuSE 1.0, MuTect2, SomaticSniper and VarScan2, which are chosen as the somatic mutation callers in the GDC DNA-seq analysis pipeline (https://docs.gdc.cancer.gov/Data/Bioinformatics_Pipelines/DNA_Seq_Variant_Calling_Pipeline/). Compared to MuSE 1.0, MuSE 2.0 with 80 cores reduces the time cost of SNV calling from ∼40 hours per pair of tumor-normal WGS data down to less than 1 hour, and from 2-4 hours per pair of tumor-normal WES data down to 4-5 minutes (~50-60 times speedup). It is also faster than three other methods (up to 60 times), i.e., MuTect2, VarScan2 and SomaticSniper, for both WGS and WES data. These results show that MuSE 2.0 is a time-efficient tool and is expected to remove somatic mutation calling as a time-consuming obstacle for cancer genomic studies and clinicians decision making. MuSE 1.0 was adopted in multiple large-scale pipelines, including as a major contributing caller to reach final consensus calls by the TCGA PanCanAtlas project across 13,000 tumor samples, and the ICGC Pan-Cancer Analysis of Whole Genomes (PCAWG) initiative across 2,700 tumor samples. We therefore expect MuSE 2.0 to significantly accelerate the variant calling process and benefit the scientific and clinical communities. MuSE 2.0 is implemented in C++ and is freely available at GitHub https://github.com/wwylab/MuSE. Citation Format: Shuangxi Ji, Tong Zhu, Ankit Sethia, Matthew D. Montierth, Wenyi Wang. Accelerated somatic mutation calling tool for whole-genome and whole-exome sequencing data from heterogenous tumor samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2070.
Abstract 4979: Evaluation of heme inhibitory therapy in combination with radiation of lung cancer
Authors: Narges Salamat, Tianyuan Wang, Eranda Berisha, Maria Del Carmen Chacon Castro, Adnin Ashrafi, Debabrata Saha, Ralph P. Mason, Li Liu, Li Zhang
Journal: Cancer Research (2023)

Abstract Lung cancer is the leading cause of cancer-related death in the United States, with a 5-year survival rate of less than 25%. While most lung cancer patients receive radiation therapy, radioresistance severely impacts treatment outcomes. Thus, development of therapeutics to potentiate durable response to radiation therapy may be key to improving treatment outcomes. Research in our lab has previously implicated heme, a central biosynthetic molecule with important functions in diverse molecular and cellular processes, in lung cancer development and progression. To target heme, we designed heme-sequestering protein 2 (HeSP2) which displays potent anti-tumor activity in mouse tumor models. By decreasing tumor metabolic demand through heme sequestration, HeSP2 can significantly alleviate tumor hypoxia, a dominant radioresistance mechanism. Tumor hypoxia correlates with poor clinical outcomes by acting via multiple mechanisms such as inhibiting radiation-induced DNA damage and inducing the HIF-1 pathway that leads to antioxidant generation. Here, our preliminary data show that HeSP2 potentiates the antitumor efficacy of ionizing radiation. To see the effect of HeSP2 in combination with radiotherapy, in summary we subcutaneously implanted A549-luc, NSCLC cell lines with mutation in Kras and KLB1 in SCID mice. After 1-2 weeks mice were treated with saline (Control), HeSP2(25 mg/kg, i.v, twice a week), radiation (5 Gray, once per week at week 2 and 3), and HeSP2 combined with radiation (25 mg/kg, i.v, twice a week plus 5 Gray, once per week at week 2 and 3. Tumor tissues were harvested, processed and paraffin embedded for immunohistochemistry (IHC). Preliminary results indicate HeSP2 in combination with radiation reduce the levels of multiple angiogenic markers and vascular markers as well as microvessel density. These results indicate that heme sequestration in combination with radiation can be an effective strategy for suppressing lung tumors. Citation Format: Narges Salamat, Tianyuan Wang, Eranda Berisha, Maria Del Carmen Chacon Castro, Adnin Ashrafi, Debabrata Saha, Ralph P. Mason, Li Liu, Li Zhang. Evaluation of heme inhibitory therapy in combination with radiation of lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4979.
Abstract 3973: Precision RNAi using synthetic shRNAmir target sites
Authors: Ralph Neumüller, Thomas Hoffmann, Alexandra Hörmann, Maja Corcokovic, Johannes Zuber
Journal: Cancer Research (2023)

Abstract Genetic loss-of-function methods including short-hairpin RNAs (shRNAs) and CRISPR are key methods for target gene validation across a variety of different disease areas. While these methods have revolutionized target gene discovery and characterization, both methods suffer from limitations in the context of in vivo target validation due to off-target effects and insufficient knock-down for shRNAs and resistant clones for CRISPR. In this study, we describe a method, artificial RNA interference (ARTi) that overcomes these limitations by fundamentally changing the basic experimental strategy of RNAi-based loss-of-function studies. Instead of newly designing gene-specific shRNA for individual target genes, ARTi utilizes ultra-effective and selective artificial miRNA-based shRNAs that do not match any transcribed gene in the target genome. In addition, these sequences are optimized for ultra-efficient miRNA processing and knockdown of synthetic target genes, and are deeply characterized to not trigger major off-target effects, enabling highly stringent target validation in vivo with unprecedented temporal control, selectivity and potency. We validate the approach by studying the in vitro and in vivo phenotypes of EGFR, KRAS and STAG1, genes relevant to cancer biology. This loss-of-function strategy will enable novel experimental strategies in therapeutic target validation and will be instrumental in guiding the lead optimization process by establishing genetic benchmark phenotypes. Citation Format: Ralph Neumüller, Thomas Hoffmann, Alexandra Hörmann, Maja Corcokovic, Johannes Zuber. Precision RNAi using synthetic shRNAmir target sites. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3973.
Abstract 617: Oncogenic CXCL10 triggers CD8+ T cell exhaustion in ovarian cancer
Authors: Runying Long, Tao Ding, Michelle K.L Siu, David W Chan, Jiangnan He, Annie NY Cheung, Kwan Man, Hextan YS NGAN, Karen KL Chan
Journal: Cancer Research (2023)

Abstract Ovarian cancer is one of the most severe gynecologic malignancies with high mortality. Although programmed cell death 1 (PD-1) or PD-ligand 1 (PD-L1) immune checkpoint blockade (ICBs) has been used therapeutically in gynecologic cancers and has a clinically significant response in endometrial cancer, the response rate remains poor and has no different from the conventional therapies in ovarian cancer. The highly immunosuppressive microenvironment in ovarian cancer, consisting of inhibitory ligands, suppressive mediators, and cell subsets, leads to CD8+ T cell dysfunction and exhaustion and contributes to the limited efficacy of immunotherapeutic approaches. Correlative human studies have highlighted the potential importance of chemokines on the status of CD8+ T cell infiltration into tumors and on patient survival. Here, we show that CXCL10, an IFN-γ induced chemokine, derived from ovarian cancer cells, contributes to impairing CD8+ T cell antitumor immunity by regulating CD8+ T cell exhaustion in the tumor microenvironment. Clinically, we found that CXCL10 and its receptor CXCR3 had a strong positive correlation with exhausted T cell signature genes in ovarian cancer patients in TCGA and in-house cohort. Functionally, we showed that CD8+ T cell exhaustion was induced by CXCL10 activation by CRISPRa from ovarian cancer cells, whereas inhibition by CRISPRi restored CD8+ T cell antitumor immunity ex vivo and in vivo. Mechanically, ovarian cancer cells-derived CXCL10 induced the expression of CD8+ T cells exhaustion transcription factors in a CXCR3-dependent manner, driving PD-1 and TIM-3 expression on CD8+ T cells. Therapeutically, suppressing CXCL10 secretion from ovarian cancer cells enhanced the response to anti-PD-1 immunotherapy in the orthotopic mouse model. The results suggest that selectively inhibiting the oncogenic CXCL10 production may work effectively with ICBs in ovarian cancer immunotherapy. Our findings advance the understanding of the low response rate of immunotherapy in ovarian cancer and explore the potential mechanism underlying the induction of CD8+ T cell exhaustion in the tumor microenvironment. Citation Format: Runying Long, Tao Ding, Michelle K.L Siu, David W Chan, Jiangnan He, Annie NY Cheung, Kwan Man, Hextan YS NGAN, Karen KL Chan. Oncogenic CXCL10 triggers CD8+ T cell exhaustion in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 617.
Abstract 5130: Multi-plex cytokine profiling for mice on Bleomycin induced systemic sclerosis model
Authors: Yanping Yuan, Cheng Qian, Chuanzhi Yangmeng, Li Fang, Ruiqing Yan
Journal: Cancer Research (2023)

Abstract Systemic sclerosis (SSc) is recognized as an autoimmune disorder characterized by immune dysregulation, obliterative vasculopathy, excessive accumulation of extracellular matrix, and fibrosis of the skin and other organs. It also ranks on the highest position of disease-related mortality and morbidity with an impaired quality of life among the rheumatologic illnesses. However, the immunological mechanism related to SSc remains to be elucidated systemically, which may lay for the novel therapeutic methodology. In the present study, we combined the MSD methodology and flow cytometry to landscape the chemokine or cytokine network, immunology response and signaling axis in mice on Blomycin induced SSc model. Our results provide the reference and path for the future direction of novel therapeutic reagents discovery. Citation Format: Yanping Yuan, Cheng Qian, Chuanzhi Yangmeng, Li Fang, Ruiqing Yan. Multi-plex cytokine profiling for mice on Bleomycin induced systemic sclerosis model. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5130.
Abstract 4486: Proof of principle for pharmacogenomic-guided precision oncology for pediatric malignancy
Authors: Gi Ju Lee, Seung-Won Choi, Seung Ah Choi, Hee-Jin Cho, Robyn Gartrell, Ji Won Lee, Joo Whan Kim, Nam-Gu Her, Raul Rabadan, Ki Woong Sung, Do-Hyun Nam, Seung-Ki Kim
Journal: Cancer Research (2023)

Abstract Childhood cancers are rare and clinically diverse. They are typically associated with few driver mutational events than adult cancers, constituting potential targets for patient-specific precision therapy approaches. Here, we evaluated the feasibility of using a patient-derived tumor cell (PDC) based drug screening system and integrated multi-omics data to achieve precision oncology for pediatric patients. We established a PDC library derived from a few passage-cultured tumor cells from surgically resected tumor specimens and conducted chemical screening, which composed of various target agents of major oncogenic pathways (e.g. receptor tyrosine kinase inhibitor, proteasome inhibitor and histone deacetylase etc.). Next Generation Sequencing was performed to characterize the genomic and transcriptomic traits of tumors. Overall, success of establishing PDCs of pediatric cancers was high (80.4%) and comparable to adult cancers. The amount of obtained tissue was an important factor for the success of PDC establishment; the estimated optimal weight for PDC establishment was small (1.14g) and it is noteworthy that a small amount of tumor sample is sufficient to identify the potential hit(s) of parental tumors. The platform provided therapeutic options to pediatric tumors regardless of actionable targets. Our PDC approach identified several potential gene-drug associations, including anti-PI3K/Akt agents for neuroblastomas and anti-SHH agents for sarcomas with EWSR1 fusion. Given that a considerable proportion of pediatric tumors still lack actionable targets with matched treatment options, PDC-based drug screening profiles can be an optimal therapeutic strategy for these cases. Collectively, our analysis confirmed the feasibility of PDC-based in vitro drug screening systems to guide the therapeutic strategy for pediatric patients. This approach will accelerate the preclinical research for pediatric tumors to understand their pathophysiology and investigate the potential therapeutic strategies to fulfill the future precision oncology. Citation Format: Gi Ju Lee, Seung-Won Choi, Seung Ah Choi, Hee-Jin Cho, Robyn Gartrell, Ji Won Lee, Joo Whan Kim, Nam-Gu Her, Raul Rabadan, Ki Woong Sung, Do-Hyun Nam, Seung-Ki Kim. Proof of principle for pharmacogenomic-guided precision oncology for pediatric malignancy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4486.
Abstract 592: Therapeutical antibody against LILRB2 enhances antitumor immunity by reprogramming M2 macrophage
Authors: Chen Su, Yanping Feng, Hui Zhao, Meng Zhang, Longtan Luo, Feng Hao, Jinying Ning, Guojin Wu
Journal: Cancer Research (2023)

Abstract M2 macrophage is critical in maintaining an immune-suppressive microenvironment inside the tumor. Here we developed a LILRB2 antagonist antibody KA-1769 for reprogramming M2 macrophage to M1 phenotype. KA-1769 binds to LILRB2 with higher affinity (KD=0.67nM) than MK-4830 (KD=7.4nM). And it also binds to LILRB1 with weak affinity (KD=41nM) but not to other LILR family members. KA-1769 blocks bindings of HLA-G to both LILRB1 and LILRB2. Macrophage derived from monocyte with M-CSF stimulation polarizes to M1 phenotype in the presence of KA-1769 by increasing expression of CD86, MHCII, and TNF-α and decreasing expression of CD14, CD206, CD163, and IL-10. KA-1769 accelerates T cell proliferation when co-cultured with macrophage. In a syngeneic Lewis lung carcinoma murine model with LILRB2-transgenic mice, injection of KA-1769 significantly suppressed tumor growth. It decreased the tumor's myeloid-derived suppressor cells (MDSC) and CD4+ CD25+ FoxP3+ Treg population. Based on these preclinical data, KA-1769 is an excellent therapeutical antibody for enhancing antitumor immunity. Citation Format: Chen Su, Yanping Feng, Hui Zhao, Meng Zhang, Longtan Luo, Feng Hao, Jinying Ning, Guojin Wu. Therapeutical antibody against LILRB2 enhances antitumor immunity by reprogramming M2 macrophage [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 592.
Abstract 1683: Ether phospholipids metabolism is a latent vulnerability for pancreatic cancer resistance
Authors: Ziheng Chen, I-Lin Ho, Melinda Soeung, Er-Yen Yen, Johnathon Rose, Sanjana Srinivasan, Angela Deem, Sisi Gao, Haoqiang Ying, Giulio Draetta
Journal: Cancer Research (2023)

Abstract Mitochondria are hubs where bioenergetics, redox homeostasis, and anabolic metabolism pathways integrate through a tightly coordinated flux of metabolites. The essential contributions of mitochondrial metabolism to fuel tumor growth and resistance to therapy are now evident in multiple contexts. However, targeting of mitochondrial metabolism in the clinical setting has repeatedly failed, owing to a narrow therapeutic window and the remarkable ability of tumor cells to activate compensatory metabolic programs. Thus, it is essential to uncover additional mechanisms that may render cancer cells selectively susceptible to treatment and those that enable them to survive when exposed to mitochondrial metabolism-targeted drugs. Here, using pancreatic ductal adenocarcinoma (PDAC) as a disease model, we report that cellular and, in particular, mitochondrial lipid composition affects the sensitivity of cancer cells to pharmacological inhibition of electron transport chain complex I. Metabolomic, including lipidomic, analyses of patient-derived PDAC models uncovered a critical role for monounsaturated fatty acids (MUFAs) and demonstrated that MUFA-linked ether phospholipids have a critical role to sustain homeostasis of mitochondrial reactive oxygen species (ROS). Blocking de novo ether phospholipid biosynthesis in the peroxisomes, sensitized PDAC cells to mitochondrial complex I inhibition by inducing mitochondrial ROS and lipid peroxidation. Biochemical analysis revealed a role of ether phospholipids in the assembly of mitochondrial supercomplexes and ROS production. Together, our data identify an ether phospholipid-dependent mechanism that regulates mitochondrial redox control and contributes to the sensitivity of PDAC cells to complex I inhibition. These findings might lead to novel approaches to target mitochondrial metabolism in cancer cells. Citation Format: Ziheng Chen, I-Lin Ho, Melinda Soeung, Er-Yen Yen, Johnathon Rose, Sanjana Srinivasan, Angela Deem, Sisi Gao, Haoqiang Ying, Giulio Draetta. Ether phospholipids metabolism is a latent vulnerability for pancreatic cancer resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1683.
Abstract 1041: Circulating tumor (ct)DNA molecular response rate (MRR) as a potential surrogate for radiologic objective response rate (ORR): A meta-analysis of immunotherapy studies
Authors: Qu Zhang, Andy Houseman, Sammy Yuan, Joe Harding, Helen Zhou, Bin Feng, Michael L. Washburn
Journal: Cancer Research (2023)

Abstract Background: Previous studies have shown that ctDNA MR defined by 50% reduction of ctDNA levels after immune checkpoint inhibitor (ICI) treatment is significantly associated with improved survival. However, discordance between MR and radiologic response was observed, hindering the potential use of MR as a surrogate endpoint. We report a meta-analysis of MR rate (MRR) and radiologic objective response rate (ORR) with ICI intervention. The relationship between MRR difference and hazard ratio of survival has also been assessed using two independent approaches. Methods: MRR, ORR and overall survival (OS) data were compiled from 9 study arms where metastatic solid tumors were treated by ICI. Weighted least squares linear regression method was used to study the relationship between MRR and ORR. Patient level MR and OS data were downloaded from the original report (Set 1) or by digitizing Kaplan-Meier plot using Guyot algorithm (Set 2). The correlation of MRR difference between two arms and hazard ratio for OS was assessed using samples generated by bootstrapping with replacement. Similarly, a parametric simulation by fitting a piecewise exponential curve was also performed to confirm the above finding. Results: A total of 958 patients were eligible for this analysis. A significant correlation between MRR and ORR was identified across 9 study arms after adjusting sample size (Adjusted R2=0.91, P&amp;lt;0.0001). Under a hypothetical scenario of two randomized study arms, an inverse correlation between MRR difference and hazard ratio was observed using both bootstrapping and parametric simulation approaches across different conditions. A stronger negative trend was found in Set 1 compared with Set 2, where MR showed a better association with OS in the former (HR=0.27 versus HR=0.41) Conclusions: This meta-analysis showed for the first time that ctDNA molecular response rate may be a surrogate for radiologic objective response rate in ICI and could enable early decision making. Since most of the data analyzed here is from patients with non-small cell lung cancer, the extrapolation of these findings to other tumor types needs further validation. Citation Format: Qu Zhang, Andy Houseman, Sammy Yuan, Joe Harding, Helen Zhou, Bin Feng, Michael L. Washburn. Circulating tumor (ct)DNA molecular response rate (MRR) as a potential surrogate for radiologic objective response rate (ORR): A meta-analysis of immunotherapy studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1041.